1. Filed of the Invention
The object of the present invention is a device and a method for the treatment of blood with selective extraction of solutes.
The object of this patent application is the filtration of blood to selectively separate and extract dissolved substances of chosen molecular size by means of extracorporeal systems designed for the separation of substances.
2. Description of Related Art
Such systems are used for the treatment of blood containing solutes with different molecular weights. Such substances are, for example, urea, of molecular weight 60 daltons, phosphate (96-97 daltons), creatinine (113 daltons), vitamin B12 (1 355 daltons), inulin (5 200 daltons), beta 2-microglobulin (12 000 daltons), and albumin (58 000 daltons).
Are hereafter termed ‘small-sized molecules’ molecules of molecular weight less than about 2 000 daltons, ‘medium-sized molecules’ molecules of molecular weight between 2 000 and 50 000 daltons, and ‘large-sized molecules’ molecules of molecular weight greater than 50 000 daltons (for example, proteins).
Such systems are often systems with extracorporeal membranes for the separation of solutes of molecular weight lower than that of albumin, applied to the treatment of renal insufficiency.
Improvements have always been sought in particular to ameliorate clearance, reduce treatment time and to make such systems simpler and less costly. The clearance of a solute is the amount of that solute in a given volume of treated blood.
In the field of dialysis, the first membranes used were highly permeable to small solutes of molecular weight up to 200 daltons. The clearance of small solutes depends on the permeability and diffusion capacity of the membrane used.
The lack of permeability of the first membranes for certain medium-sized solutes in the vitamin B12 range (1 355 daltons) was blamed for the occurrence of multiple uraemic neuropathies.
To improve the clearance of medium-sized molecules, a first response was to add to the diffusion flow through the membrane a convection flow using high flow membranes with a molecular size cut-off value of 40 000 daltons. The cut-off value of a membrane is defined as the molecular size for which no more than 10% of the solute travels through the membrane.
However, problems met in embodying this response include difficulty in controlling the ultrafiltration rate obtained by the convection flow, and the high loss of useful plasma constituents such as hormones, vitamins and amino acids.
A second response for the improvement of the clearance of medium-sized molecules was haemo-filtration, a purely convective method for the elimination of solutes by the membrane. However, this method extracts a large amount of liquid, therefore requiring a compensatory pre- and (or) post-dilution with sterile liquid, and a membrane that is highly permeable to solutes of molecular weight up to 40 000 daltons. However, in a purely convective mode, the clearance depends on the mode of dilution (pre- or post-dilution), the blood flow rate and the infusate flow rate. With conventional haemo-filtration, the clearance of small-sized molecules is poorer than that obtained in haemodialysis mode. The clearance in haemo-filtration mode could reach that of haemodialysis if the infusate flow rate, the blood flow and the membrane area were increased. However, this is impractical, increases treatment cost and results in loss of amino acids and hormones. In addition, the blood flow rate is limited, in particular in patients with poor blood access.
Concerning the clearance of small-sized molecules, when it was discovered that this clearance was limited in haemo-filtration mode, the two processes of haemo-filtration and haemodialysis were combined. This simultaneous method was known as haemo-diafiltration. However, problems that arise include difficulty in precisely controlling the haemo-filtration flow, high loss of hormones and amino acids, the complexity of the system, the large quantities of sterile liquid and dialysate necessary, and consequently the high cost of the treatment.
Thus the use of a single filter working in different operating modes still failed to solve the particular problems of loss of molecules in a certain size range, and of high treatment cost.
A proposal was then made by Drs J. C. Kingswood and F. D. Thompson of a continuous haemo-filtration with no re-injection liquid: the treatment of the ultra-filtrate was performed by a second membrane also working in spontaneous ultrafiltration. FIG. 1 represents the dialysis set-up derived from this proposal.
The procedure is to treat a first ultra-filtrate, obtained from a first hollow fibre membrane, by sending it through a second hollow fibre membrane in ultrafiltration mode. A first ultrafiltration is performed through a first high-flow membrane impermeable to molecules larger than 10 000 daltons. The apertures in the second membrane are smaller than those in the first.
As shown in FIG. 1, at the outlet from the first membrane the unfiltered liquid, mainly containing large-sized molecules, is sent to the patient for re-injection. The first ultra-filtrate containing small- and medium-sized molecules is filtered through the second membrane. The liquid not filtered by the second membrane, mainly containing medium-sized molecules, is collected in a waste bag. The second ultra-filtrate, mainly containing small-sized molecules, is re-injected in post-dilution via the patient's venous line.
This saves consuming excessive amounts of sterile liquid in post-injection, and allows re-injection in the patient of a liquid containing few medium-sized molecules.
Even so, a high loss of nutrients, amino acids, glucose and vitamins occurs, and the clearance of small ions such as potassium is poor.
Accordingly, another dialysis device was designed. It was considered that the uraemic molecules that had to be removed were of molecular weight less than 200 daltons or between 10 000 and 40 000 daltons.
This consideration gave rise to a device composed of three filters, depicted in FIG. 2.
A first filter has a cut-off value of about 40 000 daltons. The blood flows through this first filter to yield a first filtrate containing small-sized and medium-sized molecules, i.e., molecules of molecular weight less than 40 000 daltons. The solutes of mass between 10 000 and 40 000 daltons are then eliminated by ultrafiltration through the second filter, which has a cut-off value below 10 000 daltons. The second filtrate is then treated by haemo-filtration with a membrane with a cut-off value of about 200 daltons. Thus the purified filtrate, containing solutes between 200 and 10 000 daltons, is returned for post-infusion to the patient, who also receives the molecules of molecular weight greater than 40 000 daltons.
However, the clearance of all the solutes depends on the ultrafiltration rate in filter 1, which cannot exceed 30% of the blood flow, a value that is low compared with that attained in conventional haemodialysis. This raises operating costs.
Lastly, U.S. Pat. No. 6,193,681 describes an apparatus to treat septicaemia in the blood, depicted here in FIG. 3. The blood flows first through a UV irradiation device and then through a blood concentrator before re-injection in the patient. A secondary circuit is connected to a second outlet from the blood concentrator from which the fluid flows out through a filter followed by a membrane module and a dilution source, and is then injected upstream of the blood concentrator.
There is in addition an analogous problem with plasmapheresis. Therapeutic exchange plasmapheresis is carried out on patients whose plasma contains one or more harmful or toxic substances.
These solutes are eliminated from the plasma by the same principle as the elimination of solutes from blood, one difference being the greater molecular weight of the solutes to be extracted from the plasma.
Thus recurrent problems have been encountered in the design of the devices in prior art, namely:                High consumption of perfusion liquid,        High losses of nutrients, amino acids, glucose and vitamins,        Poor clearance of solutes,        High cost of devices comprising several filters and pumps.        
The problem addressed in this patent application is how to achieve selective elimination of molecules in one or more molecular weight ranges with good clearance, yet consume very small amounts of sterile liquid.
For example, for patients in a state of septicaemia, many medium-sized molecules have to be eliminated, while still maintaining satisfactory elimination of small-sized molecules. Septicaemia is characterised by abundant repeated release of specific pathogenic germs from an initial point of infection.
Another potential problem is optimally adapting such a system for long-term therapy carried out in an intensive care environment without a risk of filter clogging. Such an adaptation can be achieved by judicious choice of mode of operation of the various filters, of use and appropriate positioning of means to regulate flow rate, of controlled flow rates and of hydraulic design of the lines.